Dementia is the progressive or chronic dysfunction of cortical or subcortical functions that results in complex cognitive decline and Alzheimer's disease is the most common etiology of dementia. Currently, causal genetic mutations such as amyloid precursor protein, presenilin 1, presenilin 2 in familial Alzheimer's disease and many susceptible genes including polymorphysm of apolipoprotein E have been reported. Furthermore, genetic testings are available in person at risk for Alzheimer's disease. However, besides from results of genetic testing, there are many issues such as economics, ethics, psychological and legal. So clinician should be considered these complexities before ordering genetic test for patients with/without Alzheimer's disease.
Alzheimer Disease ; Amyloid ; Apolipoproteins ; Dementia ; Genetic Testing ; Humans ; Presenilin-1 ; Presenilin-2

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.
Activities of Daily Living ; Alzheimer Disease/genetics* ; Humans ; Mutation ; Neurodegenerative Diseases ; Presenilin-1/genetics* ; Presenilin-2/genetics*

Alzhelmer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing betaamylold (Abeta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of familial or sporadic AD have not been fully elucidated. About 10% of all cases of AD occur as autosomal dominant inherited forms of early-onset AD, which are caused by mutations in the genes encoding APP, presenilin-1 and presenilin-2. Proteolytic processing of APP by beta-gamma-secretase and caspase generates Abetaand carboxyl-terminal fragments of APP (APP-CTFs), which have been implicated in the pathogenesis of AD. The presenilins function as one of the gamma-secretases. Abetawhich is the main component of the amyloid plaques found, is known to exert neurotoxicity by accumulating free radicals, disturbing calcium homeostasis, evoking inflammatory response and activating signaling pathways. The CTFs have been found in AD patients' brain and reported to exhibit much greater neurotoxicity than Abeta. Furthermore CTFs are known to impair calcium homeostasis and learning and memory, triggering a strong inflammatory reaction through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus and in turn, affected transcription of genes including glycogen synthase kinase-3beta which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. One of the hallmarks of AD, neurofibrillary tangles (NFT), is formed by insoluble intracellular polymers of hyperphosphorylated tau that is believed to cause apoptosis by disrupting cytoskeletal and axonal transport. This review covers the processing of APP, toxic mechanisms of Abetaand CTFs of APP, presenilin and also tau in relation to the pathogenesis of AD.
Amyloid ; Apoptosis ; Axonal Transport ; Brain ; Calcium ; Cell Death ; Dementia* ; Free Radicals ; Gliosis ; Glycogen Synthase ; Homeostasis ; Learning ; Memory ; Neurofibrillary Tangles ; Plaque, Amyloid ; Polymers ; Presenilin-1 ; Presenilin-2 ; Presenilins

Apoptosis is a form of cell death in which the cells shrink and exhibit nuclear chromatin condensation and DNA fragmentation, and yet maintain membrane integrity. Many lines of evidence have shown that brain neurons are vulnerable to degeneration by apoptosis. Also it has been suggested that apoptosis is one of the mechanism contributing neuronal loss in Alzheimer's disease(AD), since the conditions in the disease(A beta peptide, oxidative stress, low energy metabolism) are the inducers that activate apoptosis. Indeed some neurons in vulnerable regions of the AD brain show DNA damage, chromatin condensation, and apoptic bodies. Consistently, mutations in AD causative genes(Amyloid precursor protein, Presenilin-1 and Presenilin-2) increase A beta peptide1-42(Abeta1-42) and sensitize neuronal cell to apoposis. However, several lines of evidence have shown that the location of neuronal loss and A beta peptide deposition is not correlated in AD brain and transgenic mice brain over-expressing Abeta1-42. Taken together, these data may indicated that A beta peptide(and other causative factors of AD) can interact with other cellular insults or risk factors to exacerbate pathological mechansim of AD through apoptosis. Thus, this review discusses possible role and mechanism of apoptosis in AD.
Alzheimer Disease* ; Amyloid beta-Peptides ; Animals ; Apoptosis* ; Brain ; Cell Death ; Chromatin ; DNA Damage ; DNA Fragmentation ; Membranes ; Mice ; Mice, Transgenic ; Neurons ; Oxidative Stress ; Presenilin-1 ; Presenilin-2 ; Risk Factors

OBJECTIVEMutations of presenilin 1 (PSEN1) gene are the most frequent cause for familial Alzheimers disease (AD). This study was set to explore potential mutation of PSEN1 gene in a Chinese family featuring early-onset Alzheimers disease (FAD).

METHODSDNA was isolated from peripheral blood samples from 17 members of the FAD family as well as 10 patients with sporadic Alzheimers disease and 100 healthy subjects. With polymerase chain reaction (PCR) and Sanger sequencing, exons 113 of the PSEN1 gene were analyzed.

RESULTSDNA sequencing has revealed a heterozygous point mutation from G to A at position 1133 (Gly378Glu) of exon 11 of PSEN1 gene in 6 members from the family, among whom 5 were patients with dementia, whilst the remaining 1 was clinically normal but under onset age. The same mutation was not found in all other patients and the normal controls.

CONCLUSIONA novel missense mutation of the PSEN1 gene, Gly378Glu, probably underlies the autosomal dominant early-onset FAD in this Chinese family.

Adult ; Aged ; Alzheimer Disease ; diagnosis ; genetics ; Base Sequence ; Female ; Humans ; Male ; Middle Aged ; Pedigree ; Presenilin-1 ; genetics

OBJECTIVETo explore the clinical phenotype and genotype in a Chinese family affected with early-onset familial Alzheimer's disease (EOFAD).

METHODSPotential mutation of beta-amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene and apolipoprotein E (APOE) gene was detected with polymerase chain reaction (PCR) and direct sequencing.

RESULTSHomozygous APOE ε 2 allele and no gene mutation of APP gene were detected in the proband (III1). A 488A>G mutation (His163Arg) of the PSEN1 gene was found in the proband and other 4 family members (IV1, IV12, IV21, V2).

CONCLUSIONA mutation (c.488A>G, p.His163Arg) of PSEN1 gene was found in a Chinese family affected with EOFAD.

Adult ; Age of Onset ; Aged ; Alzheimer Disease ; genetics ; Child ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Presenilin-1 ; genetics

Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.
Aged ; Aging ; Alzheimer Disease* ; Autophagy ; Cerebellar Ataxia* ; Drug Discovery ; Humans ; Models, Animal ; Neurons ; Pluripotent Stem Cells ; Presenilin-1 ; Stem Cells

The link of diabetes with co-occurring disorders in the brain involves complex and multifactorial pathways. Genetically engineered rodents that express familial Alzheimer's disease-associated mutant forms of amyloid precursor protein and presenilin 1 (PSEN1) genes provided invaluable insights into the mechanisms and consequences of amyloid deposition in the brain. Adding diabetes factors (obesity, insulin impairment) to these animal models to predict success in translation to clinic have proven useful at some extent only. Here, we focus on contributing factors to diabetic brain injury with the aim of identifying appropriate animal models that can be used to mechanistically dissect the pathophysiology of diabetes-associated cognitive dysfunction and how diabetes medications may influence the development and progression of cognitive decline in humans with diabetes.
Amyloid ; Brain Injuries ; Brain ; Dementia ; Diabetes Mellitus ; Humans ; Insulin ; Models, Animal ; Obesity ; Plaque, Amyloid ; Presenilin-1 ; Rodentia

OBJECTIVETo study the effect of Tiaoxin Recipe (TXR) on learning and memory related gene expression in hippocampus of senescence accelerated mice (SAM).

METHODSChanges of learning and memory related gene expression, including mineralocorticoid receptor (MR), presenile protein 1 and 2 (PS-1, PS-2), tau, APP, apoE and bcl-2 in hippocampus of SAM were determined by reverse transcription polymerase chain reaction (RT-PCR). The effect of TXR were tested. E2020 was used as the drug for control.

RESULTSCompared with those in the same aged mice, in the 5-month old SAM, levels of gene expression of MR, tau, PS-2 and APP were significantly higher, that of apo-E lower, levels of gene expression PS-1 and bcl-2 were unobviously changed; while in the 12-month old SAM, gene expression of MR and tau were higher, bcl-2 was lower and PS-1, PS-2, apoE and APP were also unobviously changed. Continuously orally taken TXR could correct the abnormality of MR, tau and apoE gene expression in hippocampus of 5-month SAM and that of MR and bcl-2 in 12-month SAM.

CONCLUSIONContinuously orally taken of TXR has the effect of regulating and correcting learning and memory related gene expression in hippocampus of 5-month and 12-month SAM.

Aging ; drug effects ; metabolism ; Animals ; Apolipoproteins E ; biosynthesis ; genetics ; Gene Expression ; Hippocampus ; metabolism ; Learning ; drug effects ; Membrane Proteins ; biosynthesis ; genetics ; Memory ; drug effects ; Mice ; Presenilin-1 ; Presenilin-2 ; tau Proteins ; biosynthesis ; genetics

The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days. On day 7, biotinylated Aβ42 was injected into mouse tail vein. At 5 hours after the injection, blood and tissues were collected. Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. And, NAM200 and NAM400 pre-treatments significantly increased sirtuin 1 expression in brain tissues, which is accompanied by the decreased brain expression of nuclear factor kappa B by 2 doses of NAM. Increased expression of AD-related genes was attenuated by the NAM treatment, which suggests that NAM supplementation may be a potential preventive strategy against AD-related deleterious changes.
Acclimatization ; Aging ; Alzheimer Disease ; Amyloid* ; Animals ; Blotting, Western ; Brain* ; Gene Expression ; Humans ; Male ; Mice* ; NF-kappa B ; Niacin ; Niacinamide* ; Presenilin-1* ; Presenilins* ; Sirtuin 1 ; Tail ; Veins*